Alkylaminoalkyl-sulfonyl-terminated β-alanineamide amino-diol compounds for treatment of hypertension

ABSTRACT

Compounds characterized generally as alkylaminoalkyl-terminated β-alanineamide amino diol derivatives are useful as renin inhibitors for the treatment of hypertension. Compounds of particular interest are those of the formula ##STR1## wherein n is two or three; wherein x is a number selected from zero, one and two; wherein R 2  is selected from hydrido, methyl, ethyl and phenyl; wherein R 3  is selected from hydrido, cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, napthylmethyl, fluoronaphthylmethyl and chloronaphthylmethyl; wherein R 5  is methyl; wherein R 7  is cyclohexylmethyl; wherein R 8  is selected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyl and vinyl; and wherein each of R 9  and R 10  is a group independently selected from methyl, ethyl and isopropyl; or a pharmaceutically-acceptable salt thereof.

This is a continuation under 37 C.F.R. 1.60, of prior application Ser.No. 08/456,356 filed on Jun. 1, 1995, now abandoned, of Gunnar J.Hanson, John S. Baran and Barbara B. Chen, which is a continuation ofapplication Ser. No. 08/157,344 filed on Nov. 11, 1993, now issued asU.S. Pat. No. 5,432,201.

FIELD OF THE INVENTION

Renin-inhibiting compounds are known for control of hypertension. Ofparticular interest herein are compounds useful as renin inhibitingagents.

BACKGROUND OF THE INVENTION

Renin is a proteolytic enzyme produced and secreted into the bloodstreamby the juxtaglomerular cells of the kidney. In the bloodstream, renincleaves a peptide bond in the serum protein angiotensinogen to produce adecapeptide known as angiotensin I. A second enzyme known as angiotensinconverting enzyme, cleaves angiotensin I to produce the octapeptideknown as angiotensin II. Angiotensin II is a potent pressor agentresponsible for vasoconstriction and elevation of cardiovascularpressure. Attempts have been made to control hypertension by blockingthe action of renin or by blocking the formation of angiotensin II inthe body with inhibitors of angiotensin I converting enzyme.

Classes of compounds published as inhibitors of the action of renin onangiotensinogen include renin antibodies, pepstatin and its analogs,phospholipids, angiotensinogen analogs, pro-renin related analogs andpeptide aldehydes.

A peptide isolated from actinomyces has been reported as an inhibitor ofaspartyl proteases such as pepsin, cathepsin D and renin [Umezawa et al,in J. Antibiot. (Tokyo), 23, 259-262 (1970)]. This peptide, known aspepstatin, was found to reduce blood pressure in vivo after theinjection of hog renin into nephrectomized rats [Gross et al, Science,175, 656 (1971)]. Pepstatin has the disadvantages of low solubility andof inhibiting acid pro eases in addition to renin. Modified pepstatinshave been synthesized in an attempt to increase the specificity forhuman renin over other physiologically important enzymes. While somedegree of specificity has been achieved, this approach has led to ratherhigh molecular weight hepta- and octapeptides [Boger et al, Nature, 303,81 (1983)]. High molecular weight peptides are generally consideredundesirable as drugs because gastrointestinal absorption is impaired andplasma stability is compromised.

Short peptide aldehydes have been reported as renin inhibitors [Kokubuet al, Biochim. Biophys. Res. Commun., 118, 929 (1984); Castro et al,FEBS Lett., 167, 273 (1984)]. Such compounds have a reactive C-terminalaldehyde group and would likely be unstable in vivo.

Other peptidyl compounds have been described as renin inhibitors. EPAppl. #128,762, published Dec. 18, 1984, describes dipeptide andtripeptide glyco-containing compounds as renin inhibitors [also seeHanson et al, Biochm. Biophys. Res. Comm., 132, 155-161 (1985), 146,959-963 (1987)]. EP Appl. #181,110, published May 14, 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #186,977published Jul. 9, 1986 describes renin-inhibiting compounds containingan alkynyl moiety, specifically a propargyl glycine moiety, attached tothe main chain between the N-terminus and the C-terminus, such asN-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-D,L-propargylglycylamino]-3(S)-hydroxy-6-methylheptanoyl]-L-isoleucinol.EP Appl. #189,203, published Jul. 30, 1986, describespeptidyl-aminodiols as renin inhibitors. EP Appl. #200,406, publishedDec. 10, 1986, describes alkylnaphthylmethylpropionylhistidylaminohydroxy alkanoates as renin inhibitors. EP Appl. -216,539,published Apr. 1, 1987, describes alkylnaphthylmethylpropionyl aminoacylaminoalkanoate compounds as renin inhibitors orally administered fortreatment of renin-associated hypertension. PCT Application No. WO87/04349, published Jul. 30, 1987, describes aminocarbonyl aminoacylhydroxyether derivatives having an alkylamino-containing terminalsubstituent and which are described as having renin-inhibiting activityfor use in treating hypertension. EP Appl. #300,189 published Jan. 25,1989 describes amino acid monohydric derivatives having analkylamino-alkylamino N-terminus and a β-alanine-histidine orsarcosyl-histidine attached to the main chain between the N-terminus andthe C-terminus, which derivatives are mentioned as useful in treatinghypertension. U.S. Pat. No. 4,902,706 which issued Feb. 13, 1990describes a series of histidineamide-containing aminoalkylaminocarbonyl-N-terminal aminodiol derivatives for use as renininhibitors. U.S. Pat. No. 5,032,577 which issued Jul. 16, 1991 describesa series of histidineamide-aminodiol-containing renin inhibitors.

Several classes of sulfonyl-containing aminodiol renin-inhibitorcompounds are known. For example, EP #229,667 published Jul. 22, 1987describes generally alkylsulfonyl histidineamide amino diolC-terminated-alkyl compounds as renin inhibitors. Australian PatentApplication #30797/89 published Sep. 7, 1989 describes alkylsulfonylhistineamide amino diol C-terminated-alkyl compounds as renininhibitors, such as (S)-α-[(S)-α-[(t-butyl-sulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4,4-dimethylpentyl]-imidazole-4-propionamideand(S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S,4RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylhexyl]imidazole-4-propionamide.U.S. Pat. No. 4,914,129 issued Apr. 3, 1990 describes sulfone-containingamino-hydroxyvaleryl compounds for use as antihypertensive agents, suchas the compoundsN-[2(S)-benzyl-3-tert-methylsulLonylpropionyl]-His-Cha-Val-n-butylamideandN-[2(R)-benzyl-3-tert-methylsulfonylpropionyl]-His-Cha-Val-n-butylamide.EP #416,373 published Mar. 13, 1991 describes alkylsulfonylhistidineamide amino diol compounds as renin-inhibitors, such as(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazol-4-propionamideand(S)-α-[(S)-α-[(tert-butylsulfonyl)methyl]-hydrocinnamamido]-N-[(1S,2R,3R/S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxybutyl]imidazol-4-propionamide.

Alkylaminoalkyl-terminated amino-diol renin-inhibitor compounds areknown. For example, U.S. Pat. No. 4,900,745 to Hanson et al which issuedFeb. 13, 1990 describes poly(aminoalkyl)aminocarbonyl amino-diol aminoacid derivatives as antihypertensive agents such asO-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α-(R)-ethyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-{N-[2-(N,N-dimethylamino)ethyl]-N-methylamino}-ethyl]-N-methylaminocarbonyl}-3-L-phenyllactyl-L-leucineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S.Pat. No. 4,902,706 to Hanson et al which issued Feb. 20, 1990 describesaminoalkylaminocarbonyl amino-diol amino acid derivatives asantihypertensive agents such asO-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl}-3-L-homophenyllactyl-α-(R)-ethyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane andO-{N-[2-(N,N-dimethylamino)ethyl]-N-methylaminocarbonyl-3-L-phenyllactyl-L-leucineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

Beta-amino-acid-containing amino-diol compounds have been described asrenin inhibitors. For example, U.S. Pat. No. 4,900,746 to Hanson et alwhich issued Feb. 13, 1990 describes ethereal N-terminal aminodiol aminoacid derivatives as antihypertensive agents such asO-[N-methyl-N-(2-methoxyethyl)aminocarbonyl]-3-L-homophenyllactyl-α-(R)-methyl-β-alanineamideof (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S.Pat. No. 4,931,429 which issued Jun. 5, 1990 describesα-aminoacyl-β-aminoacyl aminodiols as antihypertensive agents such asBoc-L-phenylalaninyl-D,L-α-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. U.S. Pat.No. 5,089,471 which issued Feb. 18, 1992 describes peptidyl β-aminoacylaminodiol carbamates as antihypertensive agents such asO-(N-morpholinocarbonyl)-3-L-phenyllactyl-α-(R)-methyl-β-alaninamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

DESCRIPTION OF THE INVENTION

Alkylaminoalkyl-sulfonyl-terminated β-alanine amino diol compounds,having utility as renin inhibitors for treatment of hypertension in asubject, constitute a family of compounds of general Formula I: ##STR2##wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containing from one to about fourcarbon atoms; wherein R⁷ is a group selected from alkyl, cycloalkylalkyland aralkyl; wherein R⁸ is a group selected from hydrido, alkyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and haloalkenyl;wherein each of R⁹ and R¹⁰ is a group independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl, aryl, aralkyl,haloaryl and haloaralkyl; and wherein any one of said R¹ through R¹¹groups having a substitutable position may be substituted with one ormore groups selected from alkyl, hydroxy, hydroxyalkyl, halo, alkoxy,alkoxyalkyl and alkenyl; or a pharmaceutically-acceptable salt thereof.

A preferred family of compounds consists of compounds of Formula Iwherein each of R¹ and R¹¹ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, N,N-dimethylaminomethyl, N,N-diethylaminomethyl,N,N-diethylaminoethyl and phenyl; wherein n is a number selected fromzero through four, inclusive; wherein x is a number selected from zero,one and two; wherein R² is selected from hydrido and alkyl; wherein R³is selected from hydrido, cycloalkylalkyl, phenylalkyl, halophenylalkyl,naphthylalkyl and halonaphthylalkyl; wherein each of R⁴ and R⁶ isindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom methyl, ethyl, n-propyl, isopropyl and n-butyl; wherein R⁷ isselected from cyclohexylmethyl and benzyl, either one of which may besubstituted with one or more groups selected from alkyl, hydroxy andalkoxy; wherein R⁸ is selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, hydroxyalkyl, alkenyl and haloalkenyl; and wherein eachof R⁹ and R¹⁰ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, alkanoyl, halophenyl, phenylalkyl, halophenylalkyl,naphthyl, halonaphthyl, naphthylalkyl and halonaphthylalkyl; or apharmaceutically-acceptable salt thereof.

A more preferred family of compounds consists of compounds of Formula iwherein each of R¹ and R¹¹ is independently selected from hydrido,methyl, ethyl, n-propyl and isopropyl; wherein n is a number selectedfrom zero through three, inclusive; wherein x is a number selected fromzero, one and two; wherein R² is selected from hydrido, methyl, ethyland n-propyl; wherein R³ is selected from hydrido, cyclohexylmethyl,benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl, chlorobenzyl,chlorophenylethyl, naphthylmethyl, naphthylethyl, fluoronaphthylmethyland chloronaphthylmethyl; wherein each of R⁴ and R⁶ is independentlyselected from hydrido and methyl; wherein R⁵ is selected from methyl,ethyl, n-propyl and isopropyl; wherein R⁷ is cyclohexylmethyl; whereinR⁸ is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl,cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, allyl and vinyl;and wherein each of R⁹ and R¹⁰ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl,propylcarbonyl, ethylcarbonyl, methylcarbonyl, phenyl, benzyl,phenylethyl, monochlorophenyl, dichlorophenyl, monofluorophenyl,difluorophenyl, monochlorophenylmethyl, monochlorophenylethyl,dichlorophenylmethyl, dichlorophenylethyl, naphthyl, monofluoronaphthyl,monochloronaphthyl, naphthylmethyl, naphthylethyl, fluoronapthylmethyland chloronaphthylethyl; or a pharmaceutically-acceptable salt thereof.

An even more preferred family of compounds consists of compounds FormulaI wherein each of R¹ and R¹¹ is independently hydrido or methyl; whereinn is a number selected from zero through three, inclusive; wherein x iszero or two; wherein R² is selected from hydrido, methyl, ethyl andn-propyl; wherein R³ is selected from hydrido, cyclohexylmethyl, benzyl,phenylethyl, phenylpropyl, fluorobenzyl, fluorophenylethyl,chlorobenzyl, chlorophenylethyl, naphthylmethyl, naphthylethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is selected from methyl and ethyl; wherein R⁷ iscyclohexylmethyl; wherein R⁸ is selected from ethyl, n-propyl, n-butyl,isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl;wherein each of R⁹ and R¹⁰ is independently selected from hydrido,methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.

A highly preferred family of compounds consists of compounds of FormulaII: ##STR3## wherein n is two or three; wherein x is a number selectedfrom zero, one and two; wherein R² is selected from hydrido, methyl,ethyl and phenyl; wherein R³ is selected from hydrido, cyclohexylmethyl,benzyl, fluorobenzyl, chlorobenzyl, fluoronaphthylmethyl, naphthylmethyland chloronaphthylmethyl; wherein R⁷ is cyclohexylmethyl; wherein R⁸ isselected from n-propyl, isobutyl, cyclopropyl, cyclopropylmethyl, allyland vinyl; wherein each of R⁹ and R¹⁰ is independently selected frommethyl, ethyl and isopropyl; or a pharmaceutically-acceptable saltthereof.

The term "hydrido" denotes a single hydrogen atom (H). This hydridogroup may be attached, for example, to an oxygen atom to form a hydroxylgroup; or, as another example, one hydrido group may be attached to acarbon atom to form a ##STR4## group; or, as another example, twohydrido groups may be attached to a carbon atom to form a --CH₂ --group. Where the term "alkyl" is used, either alone or within otherterms such as "hydroxyalkyl", the term "alkyl" embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are "lower alkyl" radicals having one to about ten carbonatoms. Most preferred are lower alkyl radicals having one to about sixcarbon atoms. The term "cycloalkyl" embraces cyclic radicals havingthree to about ten ring carbon atoms, preferably three to about sixcarbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. The terms "alkylol" and "hydroxyalkyl" embrace linear orbranched alkyl groups having one to about ten carbon atoms any one ofwhich may be substituted with one or more hydroxyl groups. The term"alkenyl" embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably three to about ten carbon atoms, andcontaining at least one carbon-carbon double bond, which carbon--carbondouble bond may have either cis or trans geometry within the alkenylmoiety. The terms "alkoxy" and "alkoxyalkyl" embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy group. The term "alkoxyalkyl" alsoembraces alkyl radicals having two or more alkoxy groups attached to thealkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylgroups. Preferred aryl groups are those consisting of one, two, or threebenzene rings. The term "aryl" embraces aromatic radicals such asphenyl, naphthyl and biphenyl. The term "aralkyl" embracesaryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl. The terms"benzyl" and "phenylmethyl" are interchangeable. Each of the termssulfide, sulfinyl, and "sulfonyl", whether used alone or linked to otherterms, denotes, respectively, the divalent radicals ##STR5## The term"alkenylalkyl" denotes a radical having a double-bond unsaturation sitebetween two carbons, and which radical may consist of only two carbonsor may be further substituted with alkyl groups which may optionallycontain additional double-bond unsaturation. For any of the foregoingdefined radicals, preferred radicals are those containing from one toabout fifteen carbon atoms.

Specific examples of alkyl groups are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl andalkynyl groups may have one unsaturated bond, such as an allyl group, ormay have a plurality of unsaturated bonds, with such plurality of bondseither adjacent, such as allene-type structures, or in conjugation, orseparated by several saturated carbons.

Also included in the family of compounds of Formula I are isomericforms, including diastereoisomers. Compounds of Formula I would beuseful to treat various circulatory-related disorders. As used herein,the term "circulatory-related" disorder is intended to embracecardiovascular disorders and disorders of the circulatory system, aswell as disorders related to the circulatory system such as ophthalmicdisorders including glaucoma. In particular, compounds of Formula Iwould be useful to inhibit enzymatic conversion of angiotensinogen toangiotensin I. When administered orally, a compound of Formula I wouldbe expected to inhibit plasma renin activity and, consequently, lowerblood pressure in a patient such as a mammalian subject (e.g., a humansubject). Thus, compounds of Formula I would be therapeutically usefulin methods for treating hypertension by administering to a hypertensivesubject a therapeutically-effective amount of a compound of Formula I.The phrase "hypertensive subject" means, in this context, a subjectsuffering from or afflicted with the effects of hypertension orsusceptible to a hypertensive condition if not treated to prevent orcontrol such hypertension. Other examples of circulatory-relateddisorders which could be treated by compounds of the invention includecongestive heart failure, renal failure and glaucoma.

Description of the Synthetic Methods for the Preparation of the ReninInhibitors of the Invention ##STR6## wherein R¹ through R¹¹, x and n areas defined above.

A suitably protected amino aldehyde 1 is treated with a Grignard reagentor other organometallic reagent, preferably vinylmagnesium bromide, toobtain the vinyl carbinol 2. This material, suitably protected, isoxidized, preferably with ozone, followed by dimethyl sulfide or zinctreatment, to give intermediate 3. The preceding process is exemplifiedin Hanson et al, J. Org. Chem., 50, 5399 (1985). This aldehyde isreacted with an organometallic reagent such as isobutylmagnesiumchloride to give intermediate 4. Compound 4 is deprotected then coupled,using standard amide/peptide coupling methodology to protected β-aminoacid derivatives 5 to give compound 6. These standard couplingprocedures such as the carbodiimide, active ester(N-hydroxysuccinimide), and mixed carbonic anhydride methods are shownin Benoiton et al, J. Org. Chem., 48, 2939 (1983) and Bodansky et al,"Peptide Synthesis", Wiley (1976). Intermediate 6 is then deprotected,then coupled to intermediate 7 or 11 or 12 using the standardamide/peptide coupling methodology, to give compounds of Formula I.Suitable protecting groups may be selected from among those reviewed byR. Geiger in "The Peptides", Academic Press, N.Y. vol. 2 (1979). Forexample, P₁ or P₃ may be Boc or Cbz; P₂ may be a typical oxygenprotective group such as acetyl or t-butyldimethylsilyl. ##STR7##wherein R¹ through R³, R⁹ through R¹¹ and n are as defined above and Ris lower alkyl or benzyl.

Intermediate 7 may be prepared according to Synthetic Scheme 2. Theaddition of thiol 9 to an acrylic ester 8 in the presence of basecatalysts such as sodium hydroxide, triethylamine orbenzyltrimethylammonium hydroxide, afforded the α,62 disubstitutedpropanoic ester 10. Compound 10 is converted into its correspondingpropanoic acid 11 via alkaline hydrolysis. Compound 10 may be convertedto either sulfone 7 or sulfoxide 12 via a two step process: oxidationwith 3-chloroperbenzoic acid (for 12) or potassium peroxomonsulfate (for7), followed by alkaline hydrolysis or hydrogenolysis (when R=benzyl).

Abbreviations: P₁ is an N-protecting group; P₂ is H or an oxygenprotecting group; P₃ is an N-protecting group.

The following Steps 1-14 constitute specific exemplification of methodsto prepare starting materials and intermediates embraced by theforegoing generic synthetic schemes. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thecompounds of Steps 1-14. All temperatures expressed are in degreesCentigrade. Compound of Example 1 was prepared by using the proceduresdescribed in the following Steps 1-14:

Step 1: Preparation of(2R,3S)-N-[(tert-Butyloxy)carbonyl]-3-amino-2-acetoxy-4-phenylbutanal

Ozone/oxygen was bubbled at -70° C. into a solution of(3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene(2.55 g, 8.0 mmol) [prepared by the method of Hanson et al, J. Org.Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deepblue color persisted. Oxygen was introduced until the blue colorcompletely faded, then 3.0 mL of Me₂ S was added and the solution wasallowed to warm to 0-5° C. and stand overnight. The solvent was removedat 0° C. under vacuum yielding the title compound as a thick yellow oilwhich was used in the following step without purification.

Step 2: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-phenyl-3,4-dihydroxy-6-methylheptane

The oil prepared in Step 1 was dissolved under nitrogen in 100 mL of dryTHF and cooled to -70° C. To this solution was added 13 mL (26 mmol) ofa 2.0M solution of isobutylmagnesium chloride in ether and the stirredmixture was allowed to warm to room temperature and stir for 2 hrs.After decomposition with MeOH/H₂ O the mixture was diluted with ether,washed with saturated NH₄ Cl solution twice, then dried and the solventsstripped off under vacuum. The residue was allowed to stand overnight in80% MeOH--H₂ O containing excess ammonium hydroxide. The MeOH wasstripped off and the mixture was extracted with ether. These extractswere combined, washed with water, dilute KHSO₄, then dried andevaporated to give 2.36 g of a yellow glass which crystallized from 50mL of pentane on standing overnight. The yellow-white powder obtainedwas recrystallized from ether-hexane and furnished the title compound(0.41 g) as white, hairy needles, mp 134-136° C., Rf (ether): singlespot, 0.6. By chromatography of the mother liquors and crystallizationof the appropriate fractions, an additional 0.22 g of product, mp138-139° C., was obtained. Anal: Calcd. for C₁₉ H₃₁ NO₄ (337.45): C,67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.

Step 3: Preparation of(2S,3R,4S)-N-[(tert-Butyloxy)carbonyl]-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The diol of Step 2, 0.27 g, was reduced in MeOH with 60 psi H₂ at 60° C.in 3 hrs using 5% Rh/C catalyst After filtering, the solvent wasstripped off and the white crystals were recrystallized from CH₂ Cl₂-hexane to furnish tiny needles of the title compound, 0.19 g, mp126-128° C.; further recrystallization gave mp 128.5-129.5° C. Rf(ether): single spot, 0.8. Anal: Calcd. for C₁₉ H₃₇ NO₄ (343.50): C,66.43; H, 10.86, N, 4.08. Found: C, 66.43; H, 11.01; N, 4.03.

Step 4: Preparation of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 3 (10 g) was dissolved 6.9N HCl in dioxane(300 mL). The mixture was stirred for 30 minutes at room temperature.The solvent was removed in vacuo and to the residue was added 5% aqueoussodium hydroxide (30 mL) until a pH of 14 was obtained. This mixture wasextracted with ether and the ether extract was washed with water andbrine, then the solvent was evaporated to give the title compound (7.3g, 100% yield). ¹ H NMR: 300 MHz spectrum consistent with proposedstructure. Anal: calcd. for C₁₄ H₂₉ NO₂ : C, 69.07; H, 12.01; N, 5.78.Found: C, 69.19; H, 12.34; N, 5.78.

Step 5: Preparation of N-Boc-α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To a solution of N-Boc-α-(R,S)-methyl-β-alanine (137 mg, 0.67 mmol) inmethylene chloride (4 mL) at -10° C. was added N-methylpiperidine (61mg, 0.61 mmol) followed by isobutylchloroformate (75 mg, 0.55 mmol).After stirring for 5 min., a solution of the amine of Step 4 inmethylene chloride (2 mL) was added. The resulting solution was stirredfor 3 hours at -10° C., followed by 2 hours at room temperature at whichtime a white solid was isolated by filteration (60 mg, 34% yield):Rf=0.3 (5% MeOH/methylene chloride, silica gel); mp 197-200°; ¹ H NMR(CDCl₃): consistent with proposed structure. Anal: Calc'd for C₂₃ H₄₄ N₂O₅ +0,25 H₂ O: C, 63.77; H, 10.35; N, 6.46. Found: C, 63.84; H, 10.50;N, 6.45.

Step 6: Preparation of α-(R)-methyl-β-alanineamide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Step 5 (53 mg, 0.12 mmol) was stirred with amixture of trifluoroacetic acid and methanol (9:1, 5 mL). The resultingsolution was allowed to stand at room temperature for 20 minutes, thenthe solvent was evaporated. The resulting oil was stirred for 2 hourswith aqueous potassium carbonate (5%, 10 mL). This mixture was thenextracted with ethyl acetate which was dried, filtered and evaporated togive the title compound (40 mg, 100%): Rf: 0.10 (5% MeOH/methylenechloride, silica gel). This material was used without furtherpurification.

Step 7: Preparation of ethyl α-methylenebenzenepropanoate

A mixture of of KOH (8.5 g) in ethanol (100 mL) was added at roomtemperature to benzylmalonic acid diethyl ester (40 g) in ethanol (80mL) and the whole was stirred at room temperature overnight, thenconcentrated by evaporation, thereafter water (14 mL) was added and thenthe mixture was acidified in an ice bath with concentrated hydrochloricacid (12.6 mL). Partitioning between water and ether was carried out,the organic phase was dried and the ether was distilled off. Then,pyridine (26 mL), piperidine (1.22 g) and paraformaldehyde (3.56 g) wereadded to the residue. The mixture was heated in an oil bath (130°) for90 minutes, cooled, water (440 mL) were added and extraction was carriedout 3 times with n-hexane (150 mL). The combined organic phases werewashed successively with water, 1N HCl, water, saturated NaHCO₃ solutionand brine. The solution was dried (MgSO₄) and evaporated to give thetitle compound as colorless oil (26 g, 85% yield). ¹ H NMR: 300 MHzspectrum consistent with proposed structure.

Step 8: Preparation of α-methylenebenzenepropanoic acid

The ethyl α-methylenebenzenepropanoate of Step 7 (4.6 g, 24.3 mmol) wasdissolved in methanol (12 mL) and then reacted with 2N potassiumhydroxide (24 mL) solution. The mixture was stirred at room temperaturefor 4 hours and concentrated by evaporation. The residue was dilutedwith water and washed with ether. The aqueous layer was acidified to pH2 with 1N HCl, and then extracted with ethyl acetate. The extracts weredried (Na₂ SO₄) and evaporated to give the title compound as colorlessoil (2.8 g, 66% yield). ¹ H NMR: 300 MHz spectrum consistent withproposed structure.

Step 9: Preparation of phenylmethyl α-methylenebenzenepropanoate

The title acid of Step 8 (5.2 g, 30 mmol) was dissolved indimethylformamide (25 mL) and cooled to 0° C. To this potassiumcarbonate (5.7 g, 41.48 mmol) was added followed by benzyl bromide (5.7g, 29.7 mmol). The mixture was stirred at room temperature overnight.The mixture was filtered and the filtrate was diluted with ethylacetate, washed with 3 times of water, brine. The solution was dried(Na₂ SO₄) and evaporated. The residue was purified by flashchromatography on silica gel, eluting with 90:10 heptane:ethyl acetateto give the pure title compound as yellow oil (4.5 g, 60% yield). ¹ HNMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd.for C₁₇ H₁₆ O₂ : C, 80.93; H, 6.39. Found: C, 80.69; H, 6.47.

Step 10: Preparation of phenylmethylα[[[2-(dimethylamino)ethyl]thio]methyl]benzenepropanoate

The oil prepared in Step 9 (1.5 g, 5.95 mmol) was dissolved under argonin methanol (22 mL). To this solution was added2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine(0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6mmol), and the mixture was stirred at room temperature for 16 hours. Thesolvent was removed on a rotary evaporator and then the residue waspurified by flash chromatography on silica gel, eluting with 20:1 CH₂Cl₂ :MeOH to give the pure title compound (0.5 g, 24% yield). ¹ H NMR:300 MHz spectrum consistent with proposed structure. Anal: calcd. forC₂₁ H₂₇ NO₂ S+0.2H₂ O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H,7.60; N, 3.98.

Step 11: Preparation of phenylmethylα-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropanoate

The title compound in Step 10 (0.5 g, 1.4 mmol) was dissolved inmethanol (7 mL) and, while cooling with ice, oxone (potassiumperoxomonosulfate) (1.3 g) in water (6 mL) were added and the whole wasstirred at room temperature overnight. The solution was diluted withwater and extracted with methylene chloride, and the extracts were dried(Na₂ SO₄) and concentrated by evaporation. The residue was purified byflash chromatography on silica gel, eluting with 20:1 CH₂ Cl₂ :MeOH togive pure title compound as white powder (400 mg, 73%). ¹ H NMR: 300 MHzspectrum consistent with proposed structure. Anal: calcd. for C₂₁ H₂₇NO₄ S: C, 64.76; H, 6.99; N, 3.60. Found: C, 64.01; H, 6.88; N, 3.41.

Step 12: Preparation of α-[[[2-(dimethylamino)ethyl]sulfonyl]methyl]benzenepropanoic acid

The title compound of Step 11 (150 mg, 0.4 mmol) was debenzylated inethanol with 5 psi H₂ at room temperature for 1.5 hours using 4% Pd/Ccatalyst. After filtering, the solvent was stripped off to give thetitle compound as white powder (110 mg, 70%yield). ¹ H NMR: 300 MHzspectrum consistent with proposed structure. Anal: calcd. for C₁₄ H₂₁NO₄ S : C, 56.16; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.99; N, 4.35.

Step 13: Preparation of α-[[[2-(dimethylamino) ethyl]thio]methyl]benzenepropanoic acid sodium salt

The title compound of Step 10 is dissolved in methanol at roomtemperature and to this is added 1 molar equivalent of IN aqueous sodiumhydroxide. This solution is allowed to stand for 2-4 hours, thenevaporated to dryness to afford the title compound. This material isused without further purification.

Step 14: Preparation ofα-[[[2-(diethylamino)ethyl]sulfonyl]methyl]benzene propanoic acid

The title compound may be prepared by substituting the2-dimethylaminoethanethiol hydrochloride in Step 10 with2-diethylaminoethanethiol hydrochloride and proceeding with Steps 11 and12 to yield the title acid.

The following working Examples are provided to illustrate synthesis ofCompounds 1-24 of the present invention and are not intended to limitthe scope thereof. Those skilled in the art will readily understand thatknown variations of the conditions and processes of the followingpreparative procedures can be used to prepare the compounds of theExamples. All temperatures expressed are in degrees Centigrade.

EXAMPLE 1 ##STR8##

The acid of Step 12 (110 mg, 0.36 mmol) was dissolved at roomtemperature in a mixture of dimethylformamide (2 mL) and pyridine (0.4mL) and to this solution was added N,N'-disuccinimidyl carbonate (84 mg,0.33 mmol) and 4-dimethylaminopyridine (4 mg). The mixture was stirredfor 3 hours, and then the title amine of Step 6 (108 mg, 0.33 mmol) wasadded, followed by diisopropylethylamine (57 mL). This mixture wasallowed to stir at room temperature for 16 hours. The solvent was thenevaporated and the residue dissolved in ethyl acetate (10 mL). Themixture was washed successively with water, saturated sodium bicarbonateand brine. The solution was dried (Na₂ SO₄) and evaporated. The residuewas purified by flash chromatography on silica gel, eluting with 96:3:1EtOAc:MeOH:NH₄ OH to give the title compound as white powder (60 mg, 30%yield). ¹ H NMR: 300 MHz spectrum consistent with proposed structure.Anal: calc'd. for C₃₃ H₅₅ N₃ O₆ S+0.4H₂ O: C, 62.29; H, 9.11; N, 6.81.Found: C, 62.20; H, 8.86; N, 6.75.

EXAMPLE 2 ##STR9##

The acid of Step 13 (170 mg, 0.64 mmol) is dissolved at room temperaturein a mixture of dimethylformamide (3 mL) and pyridine (0.6 mL) and tothis solution is added N,N'-disuccinimidyl carbonate (163 mg, 0.64 mmol)and 4-dimethylaminopyridine (6 mg). The mixture is stirred for 3 hours,and then the title amine of Step 6 (190 mg, 0.5 mmol) is added, followedby diisopropylethylamine (87 mL). This mixture is allowed to stir atroom temperature for 16 hours. The solvent is then evaporated and theresidue dissolved in ethyl acetate (15 mL). The mixture is washedsuccessively with water, saturated sodium bicarbonate and brine. Thesolution is dried (Na₂ SO₄) and evaporated. The residue is purified byflash chromatography on silica gel to give the title compound.

EXAMPLE 3 ##STR10##

The acid of Step 14(209 mg, 0.64 mmol) is dissolved at room temperaturein a mixture of dimethylformamide (3 mL) and pyridine (0.6 mL) and tothis solution is added N,N'-disuccinimidyl carbonate (163 mg, 0.64 mmol)and 4-dimethylaminopyridine (6 mg). The mixture is stirred for 3 hours,and then the title amine of Step 6 (190 mg, 0.5 mmol) is added, followedby diisopropylethylamine (87 mL). This mixture is allowed to stir atroom temperature for 16 hours. The solvent is then evaporated and theresidue dissolved in ethyl acetate (15 mL). The mixture is washedsuccessively with water, saturated sodium bicarbonate and brine. Thesolution is dried (Na₂ SO₄) and evaporated. The residue is purified byflash chromatography on silica gel to give the title compound.

Compounds 4-24, as shown in Table 1 below, may be synthesized byreference to the foregoing specific and general procedures for preparingcompounds of Formula I.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                       Compound No.                                                                         Structure                                                              __________________________________________________________________________     4                                                                                   1 #STR11##                                                              5                                                                                   2 #STR12##                                                              6                                                                                   3 #STR13##                                                              7                                                                                   4 #STR14##                                                              8                                                                                   5 #STR15##                                                              9                                                                                   6 #STR16##                                                             10                                                                                   7 #STR17##                                                             11                                                                                   8 #STR18##                                                             12                                                                                   9 #STR19##                                                             13                                                                                   0 #STR20##                                                             14                                                                                   1 #STR21##                                                             15                                                                                   2 #STR22##                                                             16                                                                                   3 #STR23##                                                             17                                                                                   4 #STR24##                                                             18                                                                                   5 #STR25##                                                             19                                                                                   6 #STR26##                                                             20                                                                                   7 #STR27##                                                             21                                                                                   8 #STR28##                                                             22                                                                                   9 #STR29##                                                             23                                                                                   0 #STR30##                                                             24                                                                                   1 #STR31##                                                             __________________________________________________________________________

BIOLOGICAL EVALUATION Human Renin Inhibition in vitro

Compounds of Formula I were evaluated as inhibitors of human renin in anin vitro assay, as follows: This human renin inhibition test has beenpreviously described in detail [Papaioannou et al., Clinical andExperimental Hypertension, A7(9), 1243-1257 (1985)]. Human renin wasobtained from the National Institute for Biological Standards, London.An incubation mixture was prepared containing the following components:in a total volume of 0.25 mL: 100 mM Tris-acetate buffer at pH 7.4,25×10⁻⁶ Goldblatt units of renin, 0.05 mL of plasma from humanvolunteers taking oral contraceptives, 6.0 mM Na-EDTA, 2.4 mMphenylmethyl sulfonyl fluoride, 1.5 mM 8-hydroxyquinoline, 0.4 mg/mLbovine serum albumin (BSA), and 0.024 mg/mL neomycin sulfate. Thismixture was incubated for two hours at 37° C. in the presence or absenceof renin inhibitors. The produced angiotensin I was determined byradioimmunoassay (New England Nuclear kit). Test compounds to be assayedwere dissolved in DMSO and diluted with 100 mM Tris-acetate buffer at pH7.4 containing 0.5% BSA to the appropriate concentration. The finalconcentration of organic solvent in the reaction mixture was less than1%. Control incubations at 37° C. were used to correct for effects oforganic solvent on renin activity. The in vitro enzymatic conversion ofangiotensinogen to angiotensin I was inhibited by test compounds of theinvention. The compound of Example #1 was found to inhibit human reninin vitro at an IC₅₀ of 44 nM.

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a mammalmay vary widely depending on the condition of the patient and otherfactors. However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 400 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 200 mg of active compound per unit dosage form. Most preferred isa dosage form containing from about 3 mg to about 100 mg of activecompound per unit dose.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations.

What is claimed is:
 1. A method to inhibit human renin to effecttreatment of a disease mediated by renin inhibition, said methodcomprising administering to a patient in need thereof atherapeutically-effective amount of a compound of Formula I: ##STR32##wherein each of R¹ and R¹¹ is a group independently selected fromhydrido, alkyl, alkylaminoalkyl and phenyl; wherein n is a numberselected from zero through five, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is a group selected from hydrido, cycloalkylalkyl,aralkyl and haloaralkyl; wherein each of R⁴ and R⁶ is a groupindependently selected from hydrido and methyl; wherein R⁵ is selectedfrom linear and branched alkyl groups containing from one to about fourcarbon atoms;; wherein R⁷ is a group selected from alkyl,cycloalkylalkyl and aralkyl; wherein R⁸ is a group selected fromhydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl andhaloalkenyl; wherein each of R⁹ and R¹⁰ is a group independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkylacyl,aryl, aralkyl, haloaryl and haloaralkyl; and wherein any one of said R¹through R¹¹ groups having a substitutable position may be substitutedwith one or more groups selected from alkyl, hydroxy, hydroxyalkyl,halo, alkoxy, alkoxyalkyl and alkenyl; or a pharmaceutically-acceptablesalt thereof.
 2. The method of claim 1 wherein each of R¹ and R¹¹ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, N,N-dimethylaminomethyl,N,N-diethylaminomethyl, N,N-diethylaminoethyl and phenyl; wherein n is anumber selected from zero through four, inclusive; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido andalkyl; wherein R³ is selected from hydrido, cycloalkylalkyl,phenylalkyl, halophenylalkyl, naphthylalkyl and halonaphthylalkyl;wherein each of R⁴ and R⁶ is independently selected from hydrido andmethyl; wherein R⁵ is selected from methyl, ethyl, n-propyl, iso-propyland n-butyl; wherein R⁷ is selected from cyclohexylmethyl and benzyl,either one of which may be substituted with one or more groups selectedfrom alkyl, hydroxy and alkoxy; wherein R⁸ is selected from hydrido,alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkenyl andhaloalkenyl; and wherein each of R⁹ and R¹⁰ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, halophenyl,phenylalkyl, halophenylalkyl, naphthyl, halonaphthyl, naphthylalkyl andhalonaphthylalkyl; or a pharmaceutically-acceptable salt thereof.
 3. Themethod of claim 2 wherein each of R¹ and R¹¹ is independently selectedfrom hydrido, methyl, ethyl, n-propyl and isopropyl; wherein n is anumber selected from zero through three, inclusive; wherein x is anumber selected from zero, one and two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, fluorobenzyl,fluorophenylethyl, chlorobenzyl, chlorophenylethyl, naphthylmethyl,naphthylethyl, fluoronaphthylmethyl and chloronaphthylmethyl; whereineach of R⁴ and R⁶ is independently selected from hydrido and methyl;wherein R⁵ is selected from methyl, ethyl, n-propyl and iso-propyl;wherein R⁷ is cyclohexylmethyl; wherein R⁸ is selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl,cyclohexylmethyl, allyl and vinyl; and wherein each of R⁹ and R¹⁰ isindependently selected from hydrido, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl,cyclopropylmethyl, cyclopropylethyl, propylcarbonyl, ethylcarbonyl,methylcarbonyl, phenyl, benzyl, phenylethyl, monochlorophenyl,dichlorophenyl, monofluorophenyl, difluorophenyl,monochlorophenylmethyl, monochlorophenylethyl, dichlorophenylmethyl,dichlorophenylethyl, naphthyl, monofluoronaphthyl, monochloronaphthyl,naphthylmethyl, naphthylethyl, fluoronapthylmethyl andchloronaphthylethyl; or a pharmaceutically-acceptable salt thereof. 4.The method of claim 3 wherein each of R¹ and R¹¹ is independentlyhydrido or methyl; wherein n is a number selected from zero throughthree, inclusive; wherein x is zero or two; wherein R² is selected fromhydrido, methyl, ethyl and n-propyl; wherein R³ is selected fromhydrido, cyclohexylmethyl, benzyl, phenylethyl, phenylpropyl,fluorobenzyl, fluorophenylethyl, chlorobenzyl, chlorophenylethyl,naphthylmethyl, naphthylethyl, fluoronaphthylmethyl andchloronaphthylmethyl; wherein each of R⁴ and R⁶ is hydrido; wherein R⁵is selected from methyl and ethyl; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from ethyl, n-propyl, n-butyl, isobutyl,cyclopropyl, cyclobutyl, cyclopropylmethyl, allyl and vinyl; whereineach of R⁹ and R¹⁰ is independently selected from hydrido, methyl,ethyl, n-propyl, isopropyl, cyclopropylmethyl, phenyl, benzyl,monochlorophenyl and dichlorophenyl; or a pharmaceutically-acceptablesalt thereof.
 5. The method of claim 4 wherein said compound is ofFormula II: ##STR33## wherein n is two or three; wherein x is a numberselected from zero, one and two; wherein R² is selected from hydrido,methyl, ethyl and phenyl; wherein R³ is selected from hydrido,cyclohexylmethyl, benzyl, fluorobenzyl, chlorobenzyl, naphthylmethyl,fluoronaphthylmethyl and chloronaphthylmethyl; wherein each of R⁴ and R⁶is hydrido; wherein R⁵ is methyl; wherein R⁷ is cyclohexylmethyl;wherein R⁸ is selected from n-propyl, isobutyl, cyclopropyl,cyclopropylmethyl, allyl and vinyl; wherein each of R⁹ and R¹⁰ isindependently selected from methyl, ethyl and isopropyl; or apharmaceutically-acceptable salt thereof.
 6. The method of claim 5wherein said compound is ##STR34## or a pharmaceutically-acceptable saltthereof.
 7. The method of claim 5 wherein said compound is ##STR35## ora pharmaceutically acceptable salt thereof.
 8. The method of claim 5wherein said compound is ##STR36## or a pharmaceutically acceptable saltthereof.